Secondary immunodeficiency due to underlying disease states, environmental exposures, and miscellaneous causes

Author
Francisco A Bonilla, MD, PhD

Section Editor
E Richard Stiehm, MD

Deputy Editor
Anna M Feldweg, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2016. &#124 This topic last updated: Dec 02, 2014.

INTRODUCTION — Immune system function is altered by many conditions which primarily impair function of other organ systems (table 1). As with primary immunodeficiency, secondary immune dysfunction leads to an increased incidence of infection and malignancy, and the occurrence of autoimmune disease.
The mechanisms and sequelae of the immune dysfunction, occurring as the result of biochemical abnormalities, environmental exposures, miscellaneous disorders, and infections other than human immunodeficiency virus (HIV) will be reviewed here. Secondary immunodeficiencies resulting from immunosuppressive agents and malignancy are discussed separately. (See "Secondary immunodeficiency induced by biologic therapies".)
Infection with the HIV and the acquired immunodeficiency syndrome (AIDS) constitute an entire discipline by themselves and are discussed separately in the appropriate topic reviews.
DISORDERS OF BIOCHEMICAL HOMEOSTASIS — Disease processes that lead to chronic imbalances in hormones, nutrients, and toxic metabolic waste products in body fluids may have profound effects on the function of one or more components of the immune system. There are a great many diagnostic entities that may be grouped under this broad heading. It may be that many have as yet unknown effects on immune function. A few disorders where clinically significant immune dysfunction is regularly encountered are presented in this section.
Diabetes mellitus — Neutrophil dysfunction underlies much of the predisposition to fungal infections found in patients with diabetes [1]. In addition, poor peripheral circulation leads to skin ulceration and diminished delivery of neutrophils to sites of microbial entry. Some characteristic infectious complications of diabetes include disseminated candidiasis, rhinopulmonary zygomycosis (mucormycosis), and malignant otitis due to P. aeruginosa. Issues related to infection in patients with diabetes mellitus are reviewed in more detail separately. (See "Susceptibility to infections in persons with diabetes mellitus".)
Dialysis and uremia — Patients receiving hemodialysis display reduced T cell function in vitro and in vivo (cutaneous anergy), diminished antibody production, and compromised neutrophil and dendritic function [1]. Compromised neutrophil function may be due in part to the use of bioincompatible dialysis membranes, resulting in impaired adherence and attenuated responses to phagocytic stimuli (see "Clinical consequences of hemodialysis membrane biocompatibility"). Low expression and/or function of immunoglobulin G (IgG) Fc receptors have also been noted. Some of these immune defects may be partly explained by the presence of high endogenous glucocorticoid levels. Patients with end-stage renal disease, regardless of dialysis treatment, have very high blood levels of soluble interleukin-2 (IL-2) receptor and this may be responsible for reducing the bioavailability of and diminishing in vitro T cell responses to IL-2 [2].
Patients undergoing chronic peritoneal dialysis do not display systemic immune defects. However, peritoneal neutrophil function is depressed as a result of the removal of opsonic factors (immunoglobulin and complement) with the dialysate, as well as directly suppressive effects of the dialysate itself [1]. These features, together with the presence of an indwelling foreign body, explain the susceptibility to bacterial peritonitis observed in these patients. (See "Pathophysiology and prevention of peritonitis in peritoneal dialysis".)
Cirrhosis — Reduced hepatic metabolism in cirrhosis leads to high levels of endogenous glucocorticoids, which may partly explain the immune dysfunction associated with liver disease. In addition, shunting of portal blood reduces the ability of hepatic Kupffer cells to clear opsonized particles, and hypocomplementemia reduces serum opsonic activity. The most common infectious complications of severe cirrhosis are sepsis and bacterial peritonitis [1]. (See "Pathogenesis of spontaneous bacterial peritonitis" and "Acquired deficiencies of the complement system".)
Malnutrition — Most studies on nutritionally-determined immunosuppression have focused on protein-energy malnutrition. This is associated with a spectrum of immune defects including cutaneous anergy, diminished T cell mitogen responses, and decreased phagocytic cell function [3]. Additional abnormalities include the following:
●The number of circulating T cells declines, while the percentage of natural killer (NK) cells rises.
●Serum immunoglobulin is normal or increased; however, specific antibody responses are impaired.
●Primary and secondary lymphoid organs are relatively depleted of cells, and lymphoid follicles are sparse.
An acute lowering of food intake may also severely affect immune function. One study, for example, found depression of circulating lymphocytes and IL-2 production following mitogen stimulation after a fast of only seven days [4].
Malnutrition predisposes to a greater incidence of clinically apparent infection and increased morbidity and mortality due to infection with the pathogens prevalent in a given geographic area. It is estimated that worldwide, for example, malnutrition leads to 10- and 30-fold increased mortality from pneumonia and gastroenteritis, respectively [3]. In Latin America, malnutrition is a contributing factor in approximately 60 percent of the deaths due to infection. In a study conducted in rural Bangladesh, the severity of malnutrition was linked to the rate of symptomatic upper respiratory infection [5]. Reduced blood levels of the hormone leptin may be an important pathway in the immune, endocrine, and neurologic dysregulation associated with starvation [6].
A similar spectrum of defects and increased susceptibility to infection has also been linked to restricted nutritional deficiencies of zinc, iron, folate, pyridoxine, and vitamin A [7].
Immune function returns to normal when proper nutritional balance is restored.
DISORDERS OF PROTEIN LOSS — Certain disorders, such as nephrotic syndrome, protein-losing enteropathies, severe dermatitis, peritoneal dialysis, and rare pulmonary diseases, can result in hypogammaglobulinemia due to loss of protein via the kidneys, intestinal tract, lymphatic system, or skin.
Hypogammaglobulinemia from protein loss may present as low immunoglobulin G (IgG) and immunoglobulin A (IgA), sometimes with near-normal immunoglobulin M (IgM). Often, antibody levels are present in low titer, and as a result, the patient may not have increased susceptibility to infection. Accelerated loss of immune globulin can be documented by giving a large bolus of intravenous immune globulin ([IVIG], 1 to 2 grams/kg) and then assessing daily IgG levels [8]. A half life, after equilibration, of less than 15 days suggests protein loss.
Nephrotic syndrome — Patients with nephrotic syndrome can develop hypogammaglobulinemia due to protein loss, as well as depressed cellular immunity due to loss of vitamin D and other serum factors [9,10]. Treatment with immunosuppressive drugs, such as glucocorticoids, further increases the risk of infection.
Hypogammaglobulinemia may be severe with total IgG less than 200 mg/dL. Infectious complications of nephrotic syndrome include recurrent respiratory tract infections, urinary tract infections, peritonitis, and sepsis, particularly with encapsulated bacteria such as Streptococcus pneumonia. Varicella infections are also problematic in patients requiring immunosuppression. Prevention includes vaccination and careful attention to early symptoms as discussed separately. (See "Overview of heavy proteinuria and the nephrotic syndrome", section on 'Infection' and "Complications of nephrotic syndrome in children", section on 'Bacterial infection'.)
Peritoneal dialysis — Many patients undergoing regular peritoneal dialysis for chronic renal disease develop hypogammaglobulinemia. This may contribute to their defective peritoneal defenses [11]. (See "Microbiology and therapy of peritonitis in continuous peritoneal dialysis" and "Clinical manifestations and diagnosis of peritonitis in peritoneal dialysis" and "Tunnel and peritoneal catheter exit site infections in continuous peritoneal dialysis".)
Protein-losing enteropathies — A variety of gastrointestinal disorders can result in protein loss and hypogammaglobulinemia. More common diseases include celiac disease, inflammatory bowel disease, and intestinal lymphangiectasia. Protein loss should be demonstrable by measurement of the alpha-1 antitrypsin clearance in the stool. Alpha-l antitrypsin has a moderately higher molecular weight than albumin (50,000), and because it is resistant to proteolysis, is not degraded in the intestinal lumen. Thus, it passes intact into the stool when there is mucosal inflammation. (See "Protein-losing gastroenteropathy", section on 'Diagnosis'.)
Intestinal lymphangiectasia — Intestinal lymphangiectasia is abnormal dilatation of intestinal mucosal lymphatic channels leading to loss of lymph with immunoglobulins and lymphocytes into the gut. The disorder may be congenital, or may arise secondarily to processes which obstruct lymph drainage of the gut or raise central venous pressure. Congenital forms may also be associated with pulmonary chylothorax and lymphedema. It may occur as a result of surgery for congenital heart disease, particularly after the Fontan procedure [12]. (See "Hypoplastic left heart syndrome", section on 'Management'.)
Hypogammaglobulinemia and lymphopenia are variable, and some patients have an increased rate of infections, including opportunistic infections. Naive CD4 and CD8 T cells are lost preferentially to memory T cells and natural killer (NK) cells, which are retained. Mitogen proliferative responses are preserved [13]. Similar alterations are observed in patients with chylothorax [14].
Patients with recurrent infections and low serum IgG may benefit from gamma globulin infusions; however, relatively large doses may be required due to ongoing intestinal loss. Replacement therapy in this setting remains controversial.
Other disorders — Other disorders that can result in hypogammaglobulinemia due to protein loss include severe dermatitis and plastic bronchitis with chylothorax [15].
TRAUMA — Trauma is associated with subsequent defects in host defense that are generally proportional to the extent of tissue injury [16]. The mechanism initiating the cascade of immune effects is thought to be the massive release of inflammatory cytokines (interleukin-1 [IL-1], tumor necrosis factor [TNF]) due to widespread activation of monocytes and macrophages by the products of cellular necrosis. The spectrum of immune defects associated with trauma is summarized in the table (table 2).
Burns — Burn trauma tends to result in a relatively greater immunosuppression than mechanical trauma, when the extent of injury is similar [17]. The reason for this is not known. In addition to depression of specific immune activation and effector mechanisms, burns also disrupt a relatively large area of nonspecific defense (the skin). This also greatly increases the risk of infection by providing microbes ready access to the interior of the body. (See "Burn wound infection and sepsis" and "Pseudomonas aeruginosa skin, soft tissue, and bone infections", section on 'Burn infections'.)
ENVIRONMENTAL EXPOSURES — Environmental exposures that can result in immune dysfunction include ionizing and ultraviolet radiation and toxic chemicals.
Ionizing radiation — Ionizing radiation (radiographs, gamma rays) damages DNA by causing single- and double-stranded breaks, as well as chemical changes in nucleotide base structure. This leads to impaired cell division as well as to somatic mutations which may be expressed.
Impaired cell division is the main mechanism of impairment of immune system function and operates in a manner entirely analogous to what has been described for chemotherapeutic immunosuppressive agents. In addition, radiation may induce apoptosis (programmed cell death) in susceptible lymphocyte populations. Somatic mutations may impair the function of cellular proteins that regulate cell division (eg, the p53 tumor suppressor gene) and lead to malignant cell growth.
Radiation induces a rapid (hours) dose-dependent decline in peripheral blood lymphocyte counts [18]. B cells are more sensitive to radiation than T cells as reflected in the depletion of germinal centers and other B cell-rich areas of irradiated lymph nodes and spleens. Lymphocyte homing and recirculation are also affected, such that lymphocytes do not properly traffic between different lymphoid organs and regions of the body. In general, T cell numbers recover more rapidly following irradiation in comparison with B cells.
Thymic cortical cells are undergoing rapid cell division and are more radiosensitive than medullary thymocytes. Other thymic cell populations (epithelial cells) are relatively radioresistant. Several decades ago, when an "enlarged" thymus was considered a risk factor for infant mortality, the thymus was irradiated to reduce its size. This frequently resulted in long-lasting depression in blood T cell counts as well as reduction in the in vitro response to mitogens [18]. In vivo cutaneous delayed-type hypersensitivity (DTH) responses were relatively preserved. However, these children showed several delayed effects including a higher rate of thymoma as well as allergic and autoimmune diseases, such as asthma, vasculitides, sarcoidosis, inflammatory bowel disease, and thyroiditis. The specific tolerance mechanisms which are affected by radiation leading to autoimmune disease have not been defined.
Primary antibody responses are most often diminished by whole body irradiation, both due to suppression of proliferation and/or induction of apoptosis in B and T cells [18]. As after thymic irradiation, DTH responses and in vitro cellular allocytotoxicity are relatively intact following whole body irradiation. In addition, most functions of mature, long-lived phagocytic cells, such as macrophages, appear to be relatively radiation-resistant.
Even regional radiation therapy applied for the treatment of malignancy can have systemic immunologic effects. Radiation treatment of lung cancer may lead to diminished T cell numbers and reduced mitogen proliferative response in vitro [19].
The increased susceptibility to infection that results from high doses of whole body irradiation arises not only from general bone marrow and lymphocyte suppression, but also from damage to local defensive barriers [18]. The gastrointestinal tract, and to a slightly lesser extent, the skin, are both organs which always sustain a high rate of cell division to replace cell loss. Irradiation interferes with cell replacement and leads to breakdown of these defensive barriers. Fatal infections may be caused not only by common pathogens, but also by normal commensal flora. (See "Treatment of radiation injury in the adult" and "Management of radiation exposure in children following a nuclear disaster".)
Measurable immunologic effects of intense radiation exposure may be long-lived. Japanese studies of survivors of atomic bomb explosions have shown the persistence over 60 years of reduced proportions of helper T cells, diminished in vitro mitogen responses and poor interleukin-2 (IL-2) production, and reduced serum levels of inflammatory cytokines [20].
Ultraviolet radiation — Ultraviolet B (UVB) radiation via sun exposure is the major determinant of risk for skin cancer [21]. This occurs through both direct mutagenesis and disruption of the cell cycle in skin epithelial cells, and from suppression of skin immune function. Chronic ultraviolet exposure leads to diminished function of all resident immune cells in the skin, including lymphocytes, mast cells, and mononuclear-derived cells, including macrophages and dendritic cells. Immunosuppressive alterations include an increased production of the antiinflammatory cytokine interleukin-10 (IL-10) and an increase in CD25+ regulatory T cells (Treg) [21,22]. These skin Treg cells have been shown to exert direct effects on skin tumorigenesis in ultraviolet-exposed mice [21]. Treg cells can be induced in the skin of neonates exposed to ultraviolet radiation and may persist for many years, possibly even into adulthood [23]. The implications for long-term health are unknown.
Toxic chemicals — Numerous environmental chemicals have been incriminated in causing harm to the immune system, giving rise to the discipline of immunotoxicology [24]. Many of these reports are anecdotal, and clinical studies frequently suffer from difficulties in the definition of insults to the immune system, small numbers, inadequacy or lack of appropriate controls, insufficient correlation between clinical problems and laboratory observations, quantitation of exposure to the substance in question, and lack of reproducibility of findings.
Nevertheless, accumulated experience supports the importance of environmental chemical exposure for immune system dysfunction [25]. The table lists some of the "xenobiotics," which have been found or suggested to cause immune defects in animals and humans and associated toxicities (table 3). In no case has a specific molecular pathophysiology been described. Many of these compounds are variably bone marrow suppressive and have also been linked to abnormalities of T cell function in vivo (thymic atrophy, circulating lymphocyte subsets, DTH) and in vitro (mitogen, antigen, and mixed lymphocyte responses, cytotoxicity). Some compounds have also been found to cause polyclonal B cell activation and have been associated with autoimmune phenomena. In some cases, exposure has been found to cause an increased incidence of infection, predominantly of the respiratory tract. Several compounds are also implicated in an increased cancer risk, either through direct mutagenic potential, decreased immune tumor surveillance, or both.
Developmental immunotoxicology has emerged as a subdiscipline [26]. Since the immune system changes significantly from the newborn period through adulthood, the immunologic insults (immunosuppression, predisposition to allergy or autoimmunity) resulting from some environmental toxic exposures have different effects depending on age (including gestational age). In general, immunologic (and other) toxic effects are more pronounced in younger developing individuals compared with adults.
ALLOGENEIC BLOOD TRANSFUSION — Blood transfusion from major histocompatibility-unrelated donors increases the rate of postoperative infection by 30 percent or more [27]. As an example, in a retrospective study of almost 10,000 consecutive hip fracture patients undergoing surgical repair, allogeneic blood transfusion was associated with a significant increase in the risk of serious postoperative bacterial infection (5.2 versus 3.7 percent with no transfusion) [28]. There was a significant dose-response relationship between the adjusted hazard ratios for these two complications and the number of units of allogeneic blood transfused. The mechanism of susceptibility is unknown, but the effect is not seen with leukocyte-depleted blood in animal studies. (See "Leukoreduction to prevent complications of blood transfusion".)
One estimate of excess mortality due to infection resulting from blood transfusion-induced immunosuppression is 125 deaths/million units. In animal models, blood transfusion also leads to accelerated tumor growth and increased mortality. This may be important in the occurrence and recurrence of malignancy in humans. Blood transfusion increases mortality by 9 percent in patients with colorectal cancer [29].
SPLENECTOMY OR HYPOSPLENISM — The hematologic and immune effects of splenectomy or hyposplenism and measures to prevent infection in patients with impaired splenic function are reviewed elsewhere. (See "Approach to the adult patient with splenomegaly and other splenic disorders", section on 'Hyposplenism and asplenia' and "Prevention of sepsis in the asplenic patient".)
NORMAL LIFE STAGES AND EVENTS — Immune function may be impaired by normal life stages and events, such as aging, pregnancy, and extreme stress.
Aging — Immune dysfunction associated with aging is reviewed separately. (See "Immune function in older adults".)
Pregnancy — Pregnant women have a higher incidence of numerous infectious diseases dependent upon cellular immunity for their control [30]. These include hepatitis A and B, influenza, herpesviruses, chlamydia, listeria, Campylobacter, tuberculosis, and several fungal, protozoan, and helminthic infections.
Depressed cellular immunity during pregnancy is assumed to have a "survival benefit" by reducing the likelihood of maternal "rejection" of the fetus, which contains potent alloantigenic stimuli derived from the father. Multiple etiologic factors have been implicated:
●Progesterone may be a major immunosuppressive factor in pregnancy. It has been shown to inhibit lymphocyte proliferation in vitro.
●A pregnancy-specific serum factor called uromodulin has been shown to inhibit B cell activity, although antibody responses are generally preserved during pregnancy.
●Depressed T cell responses to mitogens have been observed only in the presence of autologous serum, suggesting the importance of circulating suppressive factors [31].
Stress — Major life stresses such as bereavement, as well as less catastrophic stresses, such as examinations in medical school, have been associated with increased rates of respiratory tract infection, reactivation of herpesvirus infections, and increased incidence of cancer [32,33]. Similar findings occur in humans and animals during and after space flight [34]. While the space environment may play a role, this is thought to be most likely the result of a relatively extreme occupational psychological stress, with possible implications for more down-to-earth highly stressful occupations. Diminished cellular immune function has also been described in those suffering from posttraumatic stress disorder [35].
Laboratory studies have consistently shown reduced natural killer (NK) cell activity and depressed lymphocyte mitogen responses in stressed individuals. The discipline of psychoneuroimmunology is devoted to the study of these phenomena, although well-defined mechanisms of neural regulation of immunity are yet to be described. Increased production of corticotropin-releasing factor and sympathetic autonomic activity has been suggested to play a role.
It is unlikely that emotional stress alone, however severe, will commonly cause an increased incidence or severity of infection sufficient to prompt investigation of immune function. The degree to which chronic stress contributes to the public health burden of infectious disease and malignancy remains a subject of debate.
INFECTIONS (OTHER THAN HIV) — Many human pathogens have evolved sophisticated means for surviving attack by the immune systems of their hosts [36,37]. In most cases, these mechanisms selectively affect host response to the invader and are not generally immunosuppressive, with the important exception of the profound immunosuppression resulting from human immunodeficiency virus (HIV) infection. (See "The natural history and clinical features of HIV infection in adults and adolescents".)
Instances in which microbial infection leads to less profound generalized immunosuppression will be discussed here. Laboratory studies of immune function are not routinely conducted in patients with these infections.
Viral infections
Measles — Aside from HIV, measles (morbillivirus) is the only viral agent implicated in significant global immunosuppression, leading to severe, and sometimes fatal, superinfection [38,39]. Secondary immunosuppression due to measles virus infection is particularly important in the developing world, and malnutrition is an important independent risk factor for severe immune compromise, superinfection, and death from measles infection. In one retrospective study of measles fatalities in South Africa, 85 percent of deaths were mainly attributed to viral, bacterial, or fungal lung super- or co-infections [38]. The most frequent infectious complications of measles are pneumonia, gastroenteritis, otitis media, gingivostomatitis, and laryngotracheobronchitis. Pathogens included common viral agents such as herpes simplex, cytomegalovirus, parainfluenza, adenovirus, coxsackie, and respiratory syncytial virus. Bacteria included community-acquired organisms, such as Staphylococcus aureus and Streptococcus pneumoniae, as well as nosocomial pathogens, such as Klebsiella, Pseudomonas, and Acinetobacter. Mycobacterium tuberculosis and Candida albicans were also found.
Immune alterations induced by measles include T cell lymphopenia with depletion of T dependent areas of lymph nodes and spleen, cutaneous anergy, diminished in vitro T cell proliferation with mitogens or alloantigens, and diminished antibody production [39]. These effects are caused by direct infection of T cells by measles virus and by infection of dendritic cells, impairing their important antigen presenting/accessory function in T cell activation. A diminished number of circulating T cells indicates the potential for significant immune compromise and is associated with doubling of the fatality rate [38].
Herpesviruses — Herpesvirus infections can cause transient depression of cell-mediated immunity manifested by decreased in vitro proliferation with mitogens and reduced interferon-gamma production in response to mitogens during the acute phase of the illness [40]. These phenomena are most profound and long-lived with cytomegalovirus, but secondary superinfection is unusual. Herpesvirus persistence has also been implicated in the mechanisms of immunosenescence (see above) [41]. (See "Immune function in older adults", section on 'Immune risk profile and herpesviruses'.)
Bacterial infections — Infection by bacteria is not generally associated with significant secondary immunosuppression. One exception may be bacteria that produce "superantigen" toxins (eg, staphylococci, streptococci). Superantigens can bind simultaneously to major histocompatibility complex (MHC) class II antigens and to the non-antigen-binding region of T cell receptor variable regions, thereby stimulating large numbers (up to 20 percent) of T cells. These T cells then produce large amounts of inflammatory cytokines, which lead to a syndrome resembling septic shock with multisystem organ failure (eg, staphylococcal toxic shock syndrome). Following interaction with superantigens, circulating T cells first increase, then decrease. Animal studies have shown that some T cells enter a state of anergy and cannot be further activated [42]. These bacteria also produce superantigen-like molecules with distinct biologic activities, including interference with opsonophagocytosis and other neutrophil functions. Although these bacterial products are very important as virulence factors, their role in inducing any secondary immunosuppression is unclear.
Mycobacterial infections — Mycobacteria establish chronic infections and replicate within phagocytic cells (monocytes and macrophages). Several secreted and surface mycobacterial products inhibit the ability of the infected cell to kill the invader and also prevent normal cooperation with other cells in immune responses [43]. This may lead to some increase in the risk of secondary infection.
Parasite infestation — The immunosuppression resulting from protozoan infestation tends to be more pronounced than that found with other classes of microbes, with the exception of HIV. As an example, cell-mediated immunity is generally suppressed in malaria [44]. This leads to susceptibility to infections by other microbes, delayed graft rejection, and to a higher rate of various malignancies.
Some of the possible mechanisms underlying the immunosuppression occurring during parasitic infection include [44]:
●Alteration in macrophage function
●The induction of suppressor T cells
●Production of immunosuppressive factors by the parasites themselves, which may promote the first two mechanisms or may affect other aspects of immune function
A decreased capacity for antigen presentation and microbicidal activity has been demonstrated in macrophages in malaria, trypanosomiasis, and leishmaniasis. Leishmaniasis is also associated with diminished macrophage expression of MHC class II and interleukin-1 (IL-1) production, while the function of normal T cells may be suppressed when cultured together in malaria and trypanosomiasis [44,45].
Suppressor T cells have been implicated in the immune dysfunction in many parasitic diseases, but a detailed description of their phenotype and function is lacking [46,47]. Similarly, many studies have demonstrated the presence of factors in parasite culture fluids that may nonspecifically suppress lymphocyte proliferation [48] or may activate B cells polyclonally, leading to autoantibody production [44]. The chemical characteristics and function of any of these factors has not yet been determined.
Malaria — Malaria infection is one aspect of the marked association of Epstein-Barr virus (EBV) infection with Burkitt lymphoma that is observed in Africa, but not in Europe or America [49,50]. Although the seroprevalence of EBV in western countries is significant, malaria is uncommon. Plasmodia inhibit the ability of cytotoxic T cells to maintain EBV-transformed B cells under control, leading to lymphomas. (See "Clinical manifestations and treatment of Epstein-Barr virus infection", section on 'Burkitt lymphoma'.)
Other parasites — Delayed graft rejection and impaired humoral immunity have also been found in infestations with helminths, such as Trichinella and schistosomes [51-53]. Infection with Trypanosoma brucei is associated with diminished antibody responses, cutaneous anergy, and diminished in vitro T cell mitogen responses [54]. (See "Epidemiology, pathogenesis, and prevention of African trypanosomiasis".)
SUMMARY AND RECOMMENDATIONS
●Secondary immune dysfunction can result from a wide array of disease processes and presents as an increased susceptibility to infection, malignancy, and autoimmune disease (table 1). (See 'Introduction' above.)
●Chronic imbalances in blood chemistry, nutrients, and metabolic waste products can cause immune dysfunction. Examples include diabetes, cirrhosis, and malnutrition. (See 'Disorders of biochemical homeostasis' above.)
●Hypogammaglobulinemia can result from protein loss from the kidney, gastrointestinal tract, lymphatic circulation, peritoneal dialysis, and skin. (See 'Disorders of protein loss' above.)
●Trauma, including burns, can result in secondary immunodeficiency both through the disruption of physical barriers (eg, skin, gut) and through massive release of inflammatory cytokines due to widespread activation of monocytes and macrophages by the products of cellular necrosis (table 2). The degree of immune dysfunction is generally proportional to the extent of tissue injury. (See 'Trauma' above.)
●Exposure to ionizing radiation damages DNA, leading to impaired cell division and somatic mutations. Circulating lymphocytes numbers are reduced and bone marrow hemopoiesis is suppressed. Ultraviolet radiation causes immune dysfunction that is largely limited to the skin, increasing the risk for cutaneous infections and malignancies. Certain chemicals have been implicated in immune dysfunction in animals and humans (table 3). (See 'Environmental exposures' above.)
●Common life events and stages can also result in decrements in immune function. These include aging, pregnancy, and extreme psychologic stress. (See 'Normal life stages and events' above.)
●Certain infectious organisms have evolved to evade detection and killing by the host, resulting in impairment of specific immune mechanisms. (See 'Infections (other than HIV)' above.)

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REFERENCES

1	de Marie S. Diseases and drug-related interventions affecting host defence. Eur J Clin Microbiol Infect Dis 1993; 12 Suppl 1:S36.
2	Donati D, Degiannis D, Homer L, et al. Immune deficiency in uremia: interleukin-2 production and responsiveness and interleukin-2 receptor expression and release. Nephron 1991; 58:268.
3	Santos JI. Nutrition, infection, and immunocompetence. Infect Dis Clin North Am 1994; 8:243.
4	Sävendahl L, Underwood LE. Decreased interleukin-2 production from cultured peripheral blood mononuclear cells in human acute starvation. J Clin Endocrinol Metab 1997; 82:1177.
5	Zaman K, Baqui AH, Yunus M, et al. Malnutrition, cell-mediated immune deficiency and acute upper respiratory infections in rural Bangladeshi children. Acta Paediatr 1997; 86:923.
6	Faggioni R, Feingold KR, Grunfeld C. Leptin regulation of the immune response and the immunodeficiency of malnutrition. FASEB J 2001; 15:2565.
7	Corman LC. The relationship between nutrition, infection, and immunity. Med Clin North Am 1985; 69:519.
8	Stiehm ER, Ochs HD, Winkelstein JA. Immunodeficiency disorders: General considerations. In: Immunologic disorders in infants and children, 5th ed, Stiehm ER, Ochs HD, Winkelstein JA. (Eds), Elsevier/Saunders, Philadelphia 2005. p.315.
9	Harris RC, Ismail N. Extrarenal complications of the nephrotic syndrome. Am J Kidney Dis 1994; 23:477.
10	Crew RJ, Radhakrishnan J, Appel G. Complications of the nephrotic syndrome and their treatment. Clin Nephrol 2004; 62:245.
11	Akman S, Güven AG, Ince S, Yeğin O. IgG and IgG subclasses deficiency in children undergoing continuous ambulatory peritoneal dialysis and its provocative factors. Pediatr Int 2002; 44:273.
12	Ostrow AM, Freeze H, Rychik J. Protein-losing enteropathy after fontan operation: investigations into possible pathophysiologic mechanisms. Ann Thorac Surg 2006; 82:695.
13	Vignes S, Carcelain G. Increased surface receptor Fas (CD95) levels on CD4+ lymphocytes in patients with primary intestinal lymphangiectasia. Scand J Gastroenterol 2009; 44:252.
14	Orange JS, Geha RS, Bonilla FA. Acute chylothorax in children: selective retention of memory T cells and natural killer cells. J Pediatr 2003; 143:243.
15	Brogan TV, Finn LS, Pyskaty DJ Jr, et al. Plastic bronchitis in children: a case series and review of the medical literature. Pediatr Pulmonol 2002; 34:482.
16	Faist E, Schinkel C, Zimmer S. Update on the mechanisms of immune suppression of injury and immune modulation. World J Surg 1996; 20:454.
17	Barlow Y. T lymphocytes and immunosuppression in the burned patient: a review. Burns 1994; 20:487.
18	Anderson RE, Warner NL. Ionizing radiation and the immune response. Adv Immunol 1976; 24:215.
19	Uh S, Lee SM, Kim HT, et al. The effect of radiation therapy on immune function in patients with squamous cell lung carcinoma. Chest 1994; 105:132.
20	Kusunoki Y, Hayashi T. Long-lasting alterations of the immune system by ionizing radiation exposure: implications for disease development among atomic bomb survivors. Int J Radiat Biol 2008; 84:1.
21	Beissert S, Loser K. Molecular and cellular mechanisms of photocarcinogenesis. Photochem Photobiol 2008; 84:29.
22	Norval M, McLoone P, Lesiak A, Narbutt J. The effect of chronic ultraviolet radiation on the human immune system. Photochem Photobiol 2008; 84:19.
23	Muller HK, Malley RC, McGee HM, et al. Effect of UV radiation on the neonatal skin immune system- implications for melanoma. Photochem Photobiol 2008; 84:47.
24	Karol MH, Stoliker D. Immunotoxicology: past, present, and future. Inhal Toxicol 1999; 11:523.
25	Luster MI, Blank JA, Dean JH. Molecular and cellular basis of chemically induced immunotoxicity. Annu Rev Pharmacol Toxicol 1987; 27:23.
26	Dietert RR. Developmental immunotoxicology: focus on health risks. Chem Res Toxicol 2009; 22:17.
27	Dzik S, Blajchman MA, Blumberg N, et al. Current research on the immunomodulatory effect of allogeneic blood transfusion. Vox Sang 1996; 70:187.
28	Carson JL, Altman DG, Duff A, et al. Risk of bacterial infection associated with allogeneic blood transfusion among patients undergoing hip fracture repair. Transfusion 1999; 39:694.
29	Vamvakas E, Moore SB. Perioperative blood transfusion and colorectal cancer recurrence: a qualitative statistical overview and meta-analysis. Transfusion 1993; 33:754.
30	Weinberg ED. Pregnancy-associated immune suppression: risks and mechanisms. Microb Pathog 1987; 3:393.
31	Matthiesen L, Berg G, Ernerudh J, Håkansson L. Lymphocyte subsets and mitogen stimulation of blood lymphocytes in normal pregnancy. Am J Reprod Immunol 1996; 35:70.
32	Irwin M. Stress-induced immune suppression: role of brain corticotropin releasing hormone and autonomic nervous system mechanisms. Adv Neuroimmunol 1994; 4:29.
33	Glaser R, Rice J, Sheridan J, et al. Stress-related immune suppression: health implications. Brain Behav Immun 1987; 1:7.
34	Taylor GR, Konstantinova I, Sonnenfeld G, Jennings R. Changes in the immune system during and after spaceflight. Adv Space Biol Med 1997; 6:1.
35	Namazi MR. The cellular immunodeficiency associated with post-traumatic stress disorder may be the result of sympathetic overactivity and be correctable by beta-2-blockers. Neuro Endocrinol Lett 2003; 24:468.
36	Marrack P, Kappler J. Subversion of the immune system by pathogens. Cell 1994; 76:323.
37	Haase R, Kirschning CJ, Sing A, et al. A dominant role of Toll-like receptor 4 in the signaling of apoptosis in bacteria-faced macrophages. J Immunol 2003; 171:4294.
38	Beckford AP, Kaschula RO, Stephen C. Factors associated with fatal cases of measles. A retrospective autopsy study. S Afr Med J 1985; 68:858.
39	Griffin DE. Measles virus-induced suppression of immune responses. Immunol Rev 2010; 236:176.
40	Rinaldo CR Jr. Immune suppression by herpesviruses. Annu Rev Med 1990; 41:331.
41	Koch S, Larbi A, Ozcelik D, et al. Cytomegalovirus infection: a driving force in human T cell immunosenescence. Ann N Y Acad Sci 2007; 1114:23.
42	Langley R, Patel D, Jackson N, et al. Staphylococcal superantigen super-domains in immune evasion. Crit Rev Immunol 2010; 30:149.
43	Reiner NE. Altered cell signaling and mononuclear phagocyte deactivation during intracellular infection. Immunol Today 1994; 15:374.
44	Dessaint JP, Capron A. Immunodeficiencies in parasitic diseases. Immunodefic Rev 1989; 1:311.
45	Engelhorn S, Bruckner A, Remold HG. A soluble factor produced by inoculation of human monocytes with Leishmania donovani promastigotes suppresses IFN-gamma-dependent monocyte activation. J Immunol 1990; 145:2662.
46	Tarleton RL. Trypanosoma cruzi-induced suppression of IL-2 production. II. Evidence for a role for suppressor cells. J Immunol 1988; 140:2769.
47	Abe T, Colley DG. Modulation of Schistosoma mansoni egg-induced granuloma formation. III. Evidence for an anti-idiotypic, I-J-positive, I-J-restricted, soluble T suppressor factor. J Immunol 1984; 132:2084.
48	Sztein MB, Kierszenbaum F. A soluble factor from Trypanosoma brucei rhodesiense that prevents progression of activated human T lymphocytes through the cell cycle. Immunology 1991; 73:180.
49	Magrath I, Jain V, Bhatia K. Epstein-Barr virus and Burkitt's lymphoma. Semin Cancer Biol 1992; 3:285.
50	de Thé G. The etiology of Burkitt's lymphoma and the history of the shaken dogmas. Blood Cells 1993; 19:667.
51	Camus D, Nosseir A, Mazingue C, Capron A. Immunoregulation by Schistosoma mansoni. Immunopharmacology 1981; 3:193.
52	Ottesen EA, Hiatt RA, Cheever AW, et al. The acquisition and loss of antigen-specific cellular immune responsiveness in acute and chronic schistosomiasis in man. Clin Exp Immunol 1978; 33:37.
53	Feldmeier H, Gastl GA, Poggensee U, et al. Relationship between intensity of infection and immunomodulation in human schistosomiasis. I. Lymphocyte subpopulations and specific antibody responses. Clin Exp Immunol 1985; 60:225.
54	Greenwood BM, Whittle HC, Molyneux DH. Immunosuppression in Gambian trypanosomiasis. Trans R Soc Trop Med Hyg 1973; 67:846.

Topic 3946 Version 10.0

Disclosures

Disclosures: Francisco A Bonilla, MD, PhD Grant/Research/Clinical Trial Support: CSL Behring [IgG therapy (IgG)]. Consultant/Advisory Boards: Baxter [IgG therapy (IgG)]; The Cowen Group [Immune deficiency]; Gerson-Lehrman Group [Immune deficiency]; Grand Rounds Health [Immune deficiency]; Immune Deficiency Foundation [Immune deficiency]; Octapharma [IgG therapy (IgG)]. E Richard Stiehm, MD Consultant/Advisory Boards: ADMA [Hyperimmunoglobulin for immunocompromised patients (Respiratory syncytial virus immune globulin)]. Anna M Feldweg, MD Nothing to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
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